An efficient high-yield synthesis of D-ribo-phytosphingosine

Article abstract of DOI:10.1021/ol0612096

[4R-[4α(S*),5α]]-2,2-Dimethyl-4-(2-oxo-5-vinyl[1,3] dioxolan-4-yl)oxazolidine-3-carboxylic acid tert-butyl ester 5a, obtained in excellent yield and diastereoselectivity by the α-hydroxyallylation of the Garner aldehyde (4), is exploited in a novel high-yield synthesis of D-ribo-phytosphingosine (8), using microwave-enhanced cross metathesis as the key step in the chain elongation.

Full text of DOI:10.1021/ol0612096

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3303-3305
An Efficient High-Yield Synthesis of
-ribo-Phytosphingosine†
D
Marco Lombardo,* Montse Guiteras Capdevila, Filippo Pasi, and
Claudio Trombini*
Dipartimento di Chimica “G. Ciamician”, UniVersita` di Bologna, Via Selmi 2,
40126, Bologna, Italy
marco.lombardo@unibo.it; claudio.trombini@unibo.it
Received May 17, 2006
ABSTRACT
[4R-[4
diastereoselectivity by the
(8), using microwave-enhanced cross metathesis as the key step in the chain elongation.
r
(S*),5
r
]]-2,2-Dimethyl-4-(2-oxo-5-vinyl[1,3]dioxolan-4-yl)oxazolidine-3-carboxylic acid tert-butyl ester 5a, obtained in excellent yield and
r
-hydroxyallylation of the Garner aldehyde (4), is exploited in a novel high-yield synthesis of -ribo-phytosphingosine
D
As a part of our ongoing research on the stereocontrolled
synthesis of alk-1-en-3,4-diols,1 we recently proposed 3-bro-
mopropenylmethylcarbonate 1 as a novel precursor of
monoprotected diols 2 (Scheme 1)2.
in almost quantitative yields, either adopting a one-step
Barbier protocol or a two-step Grignard procedure (Scheme
2).3
Scheme 2. One-Pot Synthesis of Cyclic Carbonates 3
Scheme 1. Synthesis of Monoprotected Diols 2
Having in our hands quite a simple and efficient reaction
protocol for the R-hydroxyallylation of carbonyl compounds,
we envisioned in (S)-N-Boc-serinal acetonide 44 (Garner
aldehyde)5 an interesting substrate to approach the 2-amino-
1,3,4-triol motif present in a variety of natural products, i.e.,
phytosphingosines. To our delight, the foregoing reaction
protocol afforded cyclic carbonate 5a in 87% isolated yield
(Scheme 3).
The reaction of 1 with zinc metal in water affords a
γ-ethero-substituted allylic organometallic compound, which
promptly adds to a carbonyl compound to give 2 in very
high isolated yields. When the same reaction is carried out
with indium metal in N,N-dimethylformamide (DMF) as the
solvent, the cyclic oxazolidin-2-ones 3 are directly obtained
(3) Lombardo, M.; Pasi, F.; Trombini, C. Eur. J. Org. Chem. In press.
(4) (a) Lombardo, M.; Licciulli, S.; Trombini, C. Tetrahedron Lett. 2003,
44, 9147. (b) Lombardo, M.; Gianotti, K.; Licciulli, S.; Trombini, C.
Tetrahedron 2004, 60, 11725.
(5) Liang, X.; Andersch, J.; Bols, M. J. Chem. Soc., Perkin Trans. 1
2001, 2136.
† Dedicated to Prof. Achille Umani-Ronchi on the occasion of his 70th
birthday.
(1) Lombardo, M.; Licciulli, S.; Trombini, C. Pure Appl. Chem. 2004,
76, 657.
(2) Lombardo, M.; Pasi, F.; Tiberi, C.; Trombini, C. Synthesis 2005, 2609.
10.1021/ol0612096 CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/21/2006

where stereoselectivity is invariant with respect to temper-
ature were recently reported in the literature.7 In these cases
it was claimed that the selectivity was controlled by entropic
rather than by enthalpic factors.
Scheme 3. R-Hydroxyallylation of Garner Aldehyde
The absolute stereochemistry of the major isomer 5a is
the result of an excellent control of both facial and simple
diastereoselectivity, in analogy to the observed outcome of
the R-hydroxyallylation of 4 with 3-bromopropenyl acetate
and indium, in a synthesis of 1,4-dideoxy-1,4-L-iminoribitol.4a
With regard to simple diastereoselectivity, we have previ-
ously reported that 1 in the presence of either indium or zinc
adds to aliphatic aldehydes with high levels of anti diaste-
reopreference, independently of the E/Z composition of
starting bromide 1.2,3 A theoretical study (DFT B3LYP, basis
set: 3-21G* and 6-311G) on the simple selectivity displayed
by zinc complexes deriving from (E)- and (Z)-3-bromopro-
penyl acetate with aliphatic aldehydes is underway, and
preliminary results confirm the stereoconvergence of the two
stereoisomeric (E)- and (Z)-allylzinc complexes to the anti
adduct, due to diastereomorphic chairlike transition states.8
Since the heterosubstituent stereopattern present in 5a
perfectly matches the polar terminus structure of D-ribo-
phytosphingosine (8),9,10 a straightforward route to 8 was
envisaged, based on a cross-metathesis (CM) reaction11 with
1-tetradecene (6) to achieve the required chain elongation
process (Scheme 4).
Following a typical Grignard procedure, 3-bromopropen-
ylmethylcarbonate 1 was added at 0 °C to a suspension of
indium powder in anhydrous DMF and the heterogeneous
mixture was stirred for 1 h at 0 °C. Garner aldehyde 4 was
then added, and the reaction mixture was stirred for 3 h at
0 °C and for an additional hour at room temperature, to allow
complete cyclization of the intermediate indium alkoxides.
GC-MS analysis of the crude reaction mixture revealed the
presence of three peaks in a 91:7:2 relative ratio, corre-
sponding to 5a and two minor isomeric products on the basis
of mass analysis. The mixture of the three isomers was
isolated in 98% overall yield after purification by SiO2 flash
chromatography (Table 1, entry 1). The major stereoisomer
Scheme 4. Retrosynthetic Strategy for the Synthesis of 8
Table 1. R-Hydroxyallylation of the Garner Aldehyde
entry metal solvent temp (°C)a yield (%)b 5a:5b:5cc
1
2
3
4
5
6
In
In
In
In
Zn
Zn
DMF
DMF
DMF
THF
DMF
THF
0
-20
-60
-78
-60
-78
98
95
98
75
97
68
91:7:2
91:7:2
91:7:2
91:7:2
91:7:2
91:7:2
a Temperature of the addition step. b Isolated yields after purification by
flash chromatography. c Diastereomeric ratio determined on the crude
reaction mixture by gas chromatography.
Preliminary screening experiments in refluxing dichloro-
ethane (DCE) with 2 equiv of 6 and Grubbs first generation
catalyst A (Figure 1) did not furnish any cross-coupled
product, while Grubbs second generation catalyst B (Figure
1) afforded the desired product in 65% isolated yield after
24 h.
5a was quantitatively isolated as a white solid by crystal-
lization from diethyl ether/pentane (1:1) at -20 °C; the
absolute configuration of 5a was unambiguously established
by comparison of its optical and spectroscopical data with
the known enantiomer of the title compound,6 while no
attempt was made to assign the absolute stereochemistry of
the two minor isomers 5b and 5c. To improve the dia-
stereoselectivity of the addition reaction the possible effect
of temperature, solvent, and metal was investigated (Table
1), but to our surprise, the relative 91:7:2 diastereomeric ratio
never changed. Other examples of nucleophilic additions
(7) (a) Berardi, R.; Cainelli, G.; Galletti, P.; Giacomini, D.; Gualandi,
A.; Muccioli, L.; Zannoni, C. J. Am. Chem. Soc. 2005, 127, 10669 and
references therein. (b) Lombardo, M.; Fabbroni, S.; Trombini, C. J. Org.
Chem. 2001, 66, 1264.
(8) Bottoni, A. et al. Manuscript in preparation.
(9) Howell, A. R.; Ndakala, A. J. Curr. Org. Chem. 2002, 6, 365.
(10) Phytosphingosines are major membrane components in plants and
yeasts, and have been found to act in mammals as enzyme inhibitors and
as citotoxic agents against leukemic cell lines: (a) Schneiter, R. Bioessays
1999, 21, 1004. (b) Sharma C.; Smith, T.; Li, S.; Schroepfer, G. J., Jr.;
Needleman, D. H. Chem. Phys. Lipids 2000, 104, 1. (c) Tamiya-Koizumi,
K.; Murate, T.; Suzuki, M.; Simbulan, C. M. G.; Nakagawa, M.; Takemura,
M.; Furuta, K.; Izuta, S.; Yoshida, S. Biochem. Mol. Biol. Int. 1997, 41,
1179.
(6) 5a: mp 82-84 °C; [R]D -73 (c 1.2, CHCl3). Barret, A. G. M.;
20
Malecha, J. W. J. Chem. Soc., Prekin Trans. 1 1994, 1901: mp 82-83 °C;
[R]D +73 (c 1.2, CHCl3).
20
3304
Org. Lett., Vol. 8, No. 15, 2006

Scheme 5. Synthesis of d-ribo-Phytosphingosine
Figure 1. Grubbs first (A) and second generation (B) catalysts.
To increase the CM step efficiency and to shorten the
reaction time, we decided to test microwave (MW) heating,
as recently reported by Poulsen using N-allyl amino acid
substrates.12 Results obtained in DCE as the solvent are
reported in Table 2.
Table 2. MW-Enhanced Synthesis of 7 by Cross-Metathesisa
entry
B (%)
6 (equiv)
time (min)
7, yield (%)b
1
2
3
4
5
6
10
5
3.5
3
1
3.5
2
2
2
2
2
3
5
5
5
5
15
15
79
76
77
70
23
93
During the hydrogenation step in MeOH, a partial hy-
drolysis of the oxazolidine ring to give 11 occurred spon-
taneously. However, the final product 8 was easily obtained
by a simple acid hydrolysis with trifluoroacetic acid/water
(20:1) of the crude reaction mixture of 10 and 11. After
vacuum evaporation of excess TFA, neutralization with aq
NaHCO3, and extraction with AcOEt, 8 was isolated in 92%
overall yield starting from 7 by flash chromatography on
silica gel, using NH3/CH3OH/CHCl3 (1.5/15/85). Optical and
spectroscopic data were in excellent agreement with those
reported in the literature.13
a Power ) 200 W, T ∼ 90 °C; for temperature-time profile see the
Supporting Information. b Isolated yields after purification by flash chro-
matography.
Adopting the same reaction conditions for thermal CM,
but using MW heating, we were able to obtain 7 in 79%
isolated yield after only 5 min of irradiation at 200 W (Table
2, entry 1). Grubbs catalyst B can be reduced from 10%
down to 3.5% without appreciable reduction in overall
isolated yields (Table 2, entries 1-3), while with lower
amounts the yields dropped considerably (Table 2, entries 4
and 5). Finally, by using 3 equiv of 6 we were able to isolate
7 in 93% yield after 15 min (Table 2, entry 6). The CM
reaction favored the formation of (E)-7 in more than 80:20
E/Z ratio; however, stereochemical outcome did not matter,
since completion of the D-ribo-phytosphingosine 8 synthesis
required hydrogenation of the double bond and removal of
the protective groups.
In summary, we have reported a very efficient 5-step
synthesis of D-ribo-phytosphingosine starting from Garner
aldehyde in 75% overall isolated yield.
Acknowledgment. This work was supported by a MIUR
(Rome) PRIN project grant: “Sintesi e Stereocontrollo di
Molecole Organiche per lo Sviluppo di Metodologie Innova-
tive di Interesse Applicativo”.
Unfortunately, the simple hydrogenation of the double
bond with Pd/C in MeOH afforded a plethora of byproducts,
presumably due to the insertion of palladium metal into the
cyclic allylic carbonate moiety of 7. So we decided to remove
the carbonate protective group using basic conditions before
hydrogenation, without isolation of any intermediate (Scheme
5).
Supporting Information Available: Detailed experi-
1
mental procedures and copies of H and 13C NMR spectra
of compounds 5a, 7, and 8. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0612096
(11) For recent examples of carbon chain elongation strategies via CM
see: (a) D-erythro- and D-threo-sphingosine: Chaudhari, V. D.; Ajish
Kumar, K. S.; Dhavale, D. D. Org. Lett. 2005, 5805. (b) D-erythro-
Sphingosine: Torrsell, S.; Somfai, P. Org. Biomol. Chem. 2004, 2, 164.
(c) L-xylo- and L-arabino-phytosphingosines: Singh, O. V.; Kampf, D. J.;
Han, H. Tetrahedron Lett. 2004, 45, 7239. (d) D-erythro-Ceramide: Rai,
A. N.; Basu, A. Org. Lett. 2004, 6, 2861. (e) R-C-galactosylceramide
immunostimulants: Chen, G.; Schmieg, J.; Tsuji, M.; Franck, R. W. Org.
Lett. 2004, 6, 4077.
(13) 8: mp 100-102 °C, [R]D20 +10.3 (c 1.0, C5H5N). (a) He, L.; Byun,
H.-S.; Bittman R. J. Org. Chem. 2000, 65, 7618: [R]D +9.7 (c 0.7,
20
C5H5N). (b) Murakami, T.; Taguchi, K Tetrahedron 1999, 55, 989: mp
98-101 °C, [R]D +8.7 (c 0.8, C5H5N). (c) Imashiro, R.; Sakurai, O.;
20
Yamashita, T.; Horikawa, H. Tetrahedron 1998, 54, 10657: [R]D +9.5
20
(c 1.0, C5H5N). (d) Li, Y.-L.; Mao, X.-H.; Wu, Y.-L. J. Chem. Soc., Perkin
Trans. 1 1995, 1559: [R]D20 +8.9 (c 0.6, C5H5N). (e) Dondoni, A.; Fantin,
G.; Fogagnolo, M.; Pedrini, P. J. Org. Chem. 1990, 55, 1439: mp 98-100
°C. (f) Mulzer, J.; Brand, C. Tetrahedron 1986, 42, 5961: mp 103 °C;
(12) Poulsen, S.-A.; Bornaghi, L. F. Tetrahedron Lett. 2005, 46, 7389.
[R]D +7.9 (c 1.2, C5H5N).
20
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